Abstract:
Plasma insulin-like growth factor-1 (IGF-1) declines with age and contributes to age-related cognitive impairment. Cyclic Glycine-Proline (cGP), the metabolite of IGF-1, regulates IGF-1 bioavailability in plasma. As cognitive function declines with age, a biomarker representing IGF-1 function may help to indicate cognitive risk and to monitor cognitive status in old people. Our previous study showed that cGP/IGF-1 molar ratio represents IGF-1 function in plasma and may be a biomarker for cognitive function. I evaluated the association of plasma cGP/IGF- 1 ratio with cognitive scores of old people, the correlations between biological values and synaptic functions in rat brains, and the changes of IGF-1 and IGF binding protein (IGFBP) concentrations in human brain tissues. The plasma samples from people with impaired (n=24) and normal (n=30) cognition; brain tissues from high-fat diet (HFD) induced obese rats (n=12) and control rats (n=12); and brain tissues from Alzheimer's disease (AD) patients (n=7) and age-matched controls (n=7) were used in the project. IGF-1 and IGFBPs were quantified by ELISA, and the level of cGP was evaluated by HPLC-MS. Compared to the controls, the cognitive impaired group had lower cognitive scores, lower IGFBP-3 concentration, higher cGP concentration and higher cGP/IGF-1 molar ratio. No differences were found in age, IGF-1 concentration and IGF-1/IGFBP-3 ratio between two groups. Plasma cGP/IGF-1 ratio was strongly correlated with cognitive function, independent of age. Compared to control rats, IGF-1 and IGFBP-2 concentrations were lower in obese rat brain, with no differences in cGP level between the groups. There was a strong correlation between IGF-1 concentration and synaptic expressions. In addition, the IGF-1 level in AD human brain was lower comparing with age-matched control, while IGFBP-2, -3 level and IGF-1/IGFBP-2+3 ratio was higher. My data suggested that if furtherly confirmed by larger study, plasma cGP/IGF-1 ratio could be a novel biomarker for predicting cognitive functions in human. Different from plasma, IGF- 1 in brains may largely be bioavailable with cGP and IGFBPs playing a minor role in regulating IGF-1 function in brain. My results also demonstrated IGF-1 deficiency and IGF-1 resistance in inferior frontal gyrus (IFG) of AD patients.